Letter pubs.acs.org/OrgLett
A Stereoselective Approach toward (−)-Lepadins A−C Xiong Li,† Lingling Hu,† Junhao Jia, He Gu, Yuanliang Jia, and Xiaochuan Chen* Key Laboratory of Green Chemistry & Technology of Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064, People’s Republic of China S Supporting Information *
ABSTRACT: A new short approach to (−)-lepadins A−C has been developed based on a stereocontrolled Diels−Alder reaction employing a chiral dienophile. With this approach, (−)-lepadin B is synthesized from 5-deoxy-D-ribose in 13 steps with 14.8% overall yield. The cisdecahydroquinoline core containing five stereocenters could be rapidly constructed via stereoselective cycloaddition and subsequent five-step one-pot hydrogenation−cyclization.
L
epadins are a growing family of cis-decahydroquinoline alkaloids. Eight lepadin alkaloids have been isolated from several marine sources including the tunicate Clavelina lepadiformis1 and its predator the flatworm Prostheceraeus vittatus (lepadins A−C),1b as well as the Australian Great Barrier Reef tunicate Didemnum sp. (lepadins D−F)2 and ascidian Aplidium tabascum (lepadins F−H).3 The lepadin alkaloids are characterized by a common structural framework of a cis-decahydroquinoline ring containing a C-2 methyl group, a C-3 oxygenated (hydroxy or acyloxy) group, and a C-5 eightcarbon side chain. A major structural difference of lepadins A− C from the other members is the trans stereochemistry between the C-5 side chain and C-4a piperidine ring instead of the cis relationship (Figure 1). Lepadins A and B have shown significant in vitro cytotoxicity against several human cancer cell lines.1b Moreover, lepadin B is a potent blocker at two neuronal nicotinic acetylcholine receptors (α4β2 and α7) with IC50 values of 0.7−0.9 μM.4 The biological activities and natural scarcity of lepadin alkaloids have attracted particular attention in the field of synthetic chemistry.5 Several elegant approaches to (−)-lepadins A−C have been developed by different groups including Toyooka,6 Kibayashi,7 Ma,8 and Amat.9 In addition, a racemic formal synthesis of lepadin B and a synthesis of (+)-lepadin B were also reported by Zard10 and Charette,11 respectively. However, it is still important to explore new routes to achieve more practical and concise syntheses of lepadin alkaloids. In the context of our studies on the employment of diverse chiral dienophiles-induced Diels−Alder reactions for the enantioselective synthesis of natural products,12 we herein report a concise and efficient approach to (−)-lepadins A−C. The retrosynthetic analysis for (−)-lepadins A−C is illustrated in Scheme 1. It was envisioned that the three natural alkaloids could be accessed from bicyclic intermediate 1 through the elongation of the C-5 side chain. The critical decahydroquinoline core of 1 could be constructed from cyclohexene amine 2 via functional group manipulations followed by an intramolecular reductive amination or amine © 2017 American Chemical Society
Figure 1. Structures of natural lepadins A−H.
nucleophilic displacement. The polysubstituted cyclohexene 2 containing three stereogenic centers should be generated via an stereoselective Diels−Alder cycloaddition between l-(acylamino)-diene 3 and chiral dienophile 4, the latter of which could be prepared readily from commercially available carbohydrates. Received: August 25, 2017 Published: September 19, 2017 5372
DOI: 10.1021/acs.orglett.7b02647 Org. Lett. 2017, 19, 5372−5375
Letter
Organic Letters
cyclohexene moiety in the cycloadducts was assigned by NMR spectroscopic analysis. In the 1H NMR spectrum of the major isomer 9, the large H-2 coupling constant (dd, J = 12.0, 4.0 Hz) at 3.67 ppm indicates its axial orientation in the half chair conformation. Meanwhile, its small J value (4.0 Hz) resulting from the axial−pseudoequatorial coupling of H-2 with H-1 indicated that the substituted cyclohexene 9 had a 1,2-cis relationship. In a similar coupling constant analysis, the minor isomer 10 also shows the 1,2-cis and 2,3-trans arrangement on its trisubstituted cyclohexene core. Apparently, two cycloadducts 9 and 10 are formed both via the endo transition state relative to the ketocarbonyl group in dienophile 7 but with opposite facial selectivity. Moreover, it is assumed that the preferably controlled stereochemistry of 7 in the related Diels− Alder reactions is similar to that of the known dienophile 11, which has been employed in the synthesis of infectocaryone to prepare cycloadduct intermediate 13.12a Therefore, the absolute configuration of major isomer 9 was assigned as (1R, 2S, 3R) on the basis of comparison with the trisubstituted cyclohexene 13, and it was subsequently confirmed by the transformation of 9 into the natural products. Thus, all stereochemistry of intermediate 9 are consistent with that of (−)-lepadins A−C. Next, the deoxygenation of ketone 9 was attempted to obtain methylene product 14. Unfortunately, the attempted methods, such as Caglioti−Wolff−Kishner reduction,14 thioacetal-based reduction,15 Yamamura−Clemmensen reduction,16 and its Arimoto variant,17 all failed. Thus, simultaneous reduction of the keto- and ester carbonyl groups in 9 with LiBH4 afforded the resulting diol 15 with good stereoselectivity, which was subjected to selective primary alcohol protection to give benzyl ether 16. The deoxygenation of secondary alcohol 16 via its transformation to the appropriate derivatives followed by Barton−McCombie reaction18 or hydride reduction19 was also unsuccessful. An alternative route to complete the subsequent synthesis is required (Scheme 3). Hydrolysis of the isopropylidene group of 16 afforded triol 18, in which the less steric hydroxyl group was selectively oxidized with TEMPO to furnish methyl ketone 19. Dihydroxyl ketone 19 was directly converted to trisubstituted olefin 20 as a single stereoisomer via a diacetylation and β-elimination sequence. α,β-Unsaturated ketone 20 was submitted to a experimentally simple hydrogenation procedure, in which five consecutive transformations involving saturation of the di- and trisubstituted olefins, removal of the N-Cbz group, intramolecular cyclic imine formation, and stereoselective reduction of the imine intermediate occurred smoothly, to give two cis-2,6-substituted piperidines 21a and 21b as a pair of epimers at the acetoxy positions (dr = 3.5:1). Successive N-Boc protection and O-debenzylation of major isomer 21a afforded the known advanced intermediate (+)-22 in Amat’s synthesis of (−)-lepadins A−C.9 After oxidation of 22 to aldehyde 23, installation of the octadienyl side chain, concomitant with deacetylation, was achieved by known protocols such as the Horner−Wadsworth−Emmons reaction9 or alkenyl iodide based Suzuki coupling7 to yield 24, the common precursor of (−)-lepadin A and B.7b,8,9 Meanwhile, minor isomer 21b was subjected to similar manipulations to afford 25, the corresponding C-3 epimer of 24. Inversion of the C-3 stereocenter in 25 through the oxidation/reduction strategy8 also furnished the target 24. A final cleavage of the N-Boc group in 24 furnished (−)-lepadin B (Scheme 4). Moreover, our work also constitutes a formal total synthesis of (−)-lepadin C, as decahydroquinoline intermediate 22 may be
Scheme 1. Retrosynthetic Analysis of (−)-Lepadins A−C
Following this strategy, we began our synthesis with 5-deoxy(5) (Scheme 2). Treatment of 5 with (carboethoxy-
D-ribose
Scheme 2. Synthesis and Structural Determination of Trisubstituted Cyclohexene 9
methylene)triphenylphosphorane gave the target E-conjugated ester 6 with excellent stereoselectivity. Triol 6 was transformed to the target dienophile 7 in high yield via a one-pot procedure involving DDQ selective oxidation of allyl alcohol followed by addition of 2,2-dimethoxypropane. With chiral enone 7 in hand, the key Diels−Alder reaction between this dienophile and benzyl trans-1,3-butadiene-1-carbamate (8)13 was examined. Gratifyingly, simply heating a mixture of 7 and 8 at 80 °C in toluene afforded two cycloaddition adducts 9 (76% yield) and 10 (12% yield). The relative configuration of the trisubstituted 5373
DOI: 10.1021/acs.orglett.7b02647 Org. Lett. 2017, 19, 5372−5375
Letter
Organic Letters Scheme 3. Synthesis of cis-Decahydroquinoline Intermediate 21a and 21b
cyclization. The chiral oxygenated chain in dienophile 7 not only exerts promising stereoinduction in the cycloaddition to generate the three desired stereocenters on the six-member ring but also is quite suitable for the subsequent construction of the substituted piperidine ring. In comparison with the cleavage of the chiral moiety in our previous dienophiles12 after the cycloaddition, dienophile 7 is utilized with higher atom economy. With the approach, commercial 5-deoxy-D-ribose is easily converted to the known advanced intermediate 22 in 10 steps, from which (−)-lepadins B, A, and C can be synthesized in three to four steps following the literature protocols. This useful strategy may provide access to other related cisdecahydroquinoline alkaloids with a trans C-5 substituent group.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02647. Detailed experimental procedures and copies of 1H and 13 C NMR spectra of the compounds (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Xiaochuan Chen: 0000-0003-3901-0524 Author Contributions †
X.L. and L.H. contributed equally.
Scheme 4. Synthesis of (−)-Lepadins A−C
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by grants from the National Natural Science Foundation of China (21172153). Compound characterization was performed by the Comprehensive Specialized Laboratory Training Platform, College of Chemistry, Sichuan University, as well as Prof. Xiaoming Feng’s group, Sichuan University.
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REFERENCES
(1) (a) Steffan, B. Tetrahedron 1991, 47, 8729−8732. (b) Kubanek, J.; Williams, D. E.; De Silva, E. D.; Allen, T.; Andersen, R. J. Tetrahedron Lett. 1995, 36, 6189−6192. (2) Wright, A. D.; Goclik, E.; Konig, G. M.; Kaminsky, R. J. Med. Chem. 2002, 45, 3067−3072. (3) Davis, R. A.; Carroll, A. R.; Quinn, R. J. J. Nat. Prod. 2002, 65, 454−457. (4) Tsuneki, H.; You, Y.; Toyooka, N.; Sasaoka, T.; Nemoto, H.; Dani, A.; Kimura, I. Biol. Pharm. Bull. 2005, 28, 611−614. (5) For a review, see: Pelss, A.; Koskinen, A. M. P. Chem. Heterocycl. Compd. 2013, 49, 226−240. (6) Toyooka, N.; Okumura, M.; Takahata, H. J. Org. Chem. 1999, 64, 2182−2183. (7) (a) Ozawa, T.; Aoyagi, S.; Kibayashi, C. Org. Lett. 2000, 2, 2955− 2958. (b) Ozawa, T.; Aoyagi, S.; Kibayashi, C. J. Org. Chem. 2001, 66, 3338−3347. (8) (a) Pu, X.; Ma, D. Angew. Chem., Int. Ed. 2004, 43, 4222−4225. (b) Pu, X.; Ma, D. J. Org. Chem. 2006, 71, 6562−6572.
converted to the alkaloid in four steps following the Amat9 and Ma8 procedure relay. In conclusion, we have developed a concise and efficient approach to (−)-lepadins A−C featuring a stereoselective Diels−Alder reaction and a one-pot five-step hydrogenation− 5374
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Organic Letters (9) (a) Amat, M.; Pinto, A.; Griera, R.; Bosch. Chem. Commun. 2013, 49, 11032−11034. (b) Amat, M.; Pinto, A.; Griera, R.; Bosch, J. Chem. - Eur. J. 2015, 21, 12804−12808. (10) Kalai, C.; Tate, E.; Zard, S. Z. Chem. Commun. 2002, 1430− 1431. (11) Barbe, G.; Charette, A. J. Am. Chem. Soc. 2008, 130, 13873− 13875. (12) (a) Liu, X.; Hu, L.; Liu, X.; Jia, J.; Jiang, L.; Lin, J.; Chen, X. Org. Biomol. Chem. 2014, 12, 7603−7611. (b) Jiang, L.; Liu, X.; Yuan, P.; Zhang, Y.; Chen, X. J. Nat. Prod. 2017, 80, 805−812. (13) (a) Overman, L. E.; Taylor, G. F.; Petty, C. B.; Jessup, P. J. J. Org. Chem. 1978, 43, 2164−2167. (b) Jessup, P. J.; Petty, C. B.; Roos, J.; Overman, L. E. Org. Synth. 1980, 59, 1−9. (14) (a) Hutchins, R. O.; Milewski, C. A.; Maryanoff, B. E. J. Am. Chem. Soc. 1973, 95, 3662−3668. (b) Caglioti, L.; Magi, M. Tetrahedron 1963, 19, 1127−1131. (c) Caglioti, L. Tetrahedron 1966, 22, 487−493. (15) (a) Clarke, P. A.; Martin, W. H. C. Tetrahedron 2005, 61, 5433− 5438. (b) Monfray, J.; Gelas-Mialhe, Y.; Gramain, J.-C.; Remuson, R. Tetrahedron: Asymmetry 2005, 16, 1025−1034. (c) Li, M.; Zhou, P.; Roth, H. F. Synthesis 2007, 2007, 55−60. (d) Su, D.; Wang, X.; Shao, C.; Xu, J.; Zhu, R.; Hu, Y. J. Org. Chem. 2011, 76, 188−194. (16) (a) Yamamura, S.; Toda, M.; Hirata, Y. Organic Syntheses, Coll. Vol. 6, 289−292. (b) Toda, M.; Hayashi, M.; Hirata, Y.; Yamamura, S. Bull. Chem. Soc. Jpn. 1972, 45, 264−266. (c) Vedejs, E. Org. React. 1975, 22, 401−422. (17) (a) Xu, S.; Toyama, T.; Nakamura, J.; Arimoto, H. Tetrahedron Lett. 2010, 51, 4534−4537. (b) Xu, S.; Unabara, D.; Uemura, D.; Arimoto, H. Chem. - Asian J. 2014, 9, 367−375. (18) (a) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans. 1 1975, 1574−1585. (b) Barton, D. H. R.; Subramanian, R. J. Chem. Soc., Perkin Trans. 1 1977, 1718−1723. (c) Muramatsu, W.; Tanigawa, S.; Takemoto, Y.; Yoshimatsu, H.; Onomura, O. Chem. Eur. J. 2012, 18, 4850−4853. (d) Meimetis, L. G.; Nodwell, M.; Yang, L.; Wang, X.; Wu, J.; Harwig, C.; Stenton, G. R.; Mackenzie, L. F.; MacRury, T.; Patrick, B. O.; Ming-Lum, A.; Ong, C. J.; Krystal, G.; Mui, A. L.-F.; Andersen, R. J. Eur. J. Org. Chem. 2012, 2012, 5195− 5207. (19) (a) Fujimoto, Y.; Tatsuno, T. Tetrahedron Lett. 1976, 17, 3325− 3326. (b) Gonzalez, A. G.; Galindo, A.; Mansilla, H.; Kesternich, V. H.; Palenzuela, J. A.; Rodriguez, M. L. J. Nat. Prod. 1990, 53, 462−465. (c) Barraclough; Spray, C. A.; Young, D. W. Tetrahedron Lett. 2005, 46, 4653−4655. (d) Frater, G.; Muller, U.; Kraft, P. Helv. Chim. Acta 2004, 87, 2750−2763. (e) Barraclough, P.; Dieterich, P.; Spray, C. A.; Young, D. W. Org. Biomol. Chem. 2006, 4, 1483−1491.
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DOI: 10.1021/acs.orglett.7b02647 Org. Lett. 2017, 19, 5372−5375
